Method and device for the release of drugs to the skin

ABSTRACT

A method of increasing the adhesiveness of a shaped pressure sensitive adhesive, comprising adding an adhesiveness and drug release increasing amount of a clay to said adhesive prior to casting of the adhesive. 
     A dermal composition comprising a drug, a pressure sensitive adhesive, an adhesiveness increasing amount of a clay and a solvent. 
     A dermal composition comprising a drug, a multipolymer of ethylene vinyl acetate, an acrylic polymer, a natural or synthetic rubber and a clay, along with optional ingredients known for use in transdermal drug delivery systems.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 07/671,709,filed Apr. 2, 1991, now U.S. Pat. No. 5,300,291, which is acontinuation-in-part of Ser. No. 295,847, filed Jan. 11, 1989; now U.S.Pat. No. 4,994,267, which is a continuation-in-part of Ser. No.07/164482 filed Mar. 4, 1988, now U.S. Pat. No. 4,814,168. The abovecited applications and patents are incorporated herein by reference. Theapplication and patent are assigned to Noven Pharmaceuticals, Inc. ofMiami, Fla.

BACKGROUND OF THE INVENTION

This invention relates to a method and device for delivering drugs tothe body through intact skin and more particularly to such devices whichincorporate a pressure sensitive adhesive and even more particularly tosuch devices having at least two phases, a phase formed of a polymermatrix having limited water solubility and, in admixture, aninterpenetrating phase of drug, polymer, liquid such as a solvent or asolid, or one or more of the foregoing.

Devices that deliver drugs through intact skin, namely the epidermis,for absorption into the body and the systemic circulatory system havebeen known for some time. Such devices can be referred to as transdermaldrug delivery devices or dermal compositions.

The purpose of such devices is to dispense a drug at a controlled, andif desired, constant rate by presenting the drug in an efficient manner,with the minimum degradation or complications from the drug or fromfailure to comply with the therapeutic regimen.

A typical prior art system using a polymer matrix involves diffusion ofthe drug at a controlled rate through the polymer. However, suchsystems, as a result of the need for a rate limiting means, are morecomplicated to manufacture. For example, U.S. Pat. Nos. 3,948,262,4,144,317 and 4,379,454 assigned to Alza and Ciba relate to transdermaldrug delivery systems. The controlled delivery devices of those patentsare structurally distinct, operate differently and accordingly, do notprovide the delivery kinetics obtained with the system of thisinvention.

It is known to deliver drugs from natural or synthetic rubbers, or fromacrylic polymers or from ethylene vinyl acetate, the drugs passing fromthe polymers by diffusion. It is also known from related applicationU.S. Pat. No. 4,814,168 to use a multipolymer adhesive incorporating adrug. It is further known from related application Ser. No. 295,847filed Jan. 11, 1989 to use a combination of a rubber, acrylic andethylene vinyl acetate polymers as the multipolymer.

It is known to use fillers in transdermal drug delivery devices. U.S.Pat. No. 4,421,737 refers to fillers used traditionally for ordinaryadhesive tapes in connection with a nitroglycerin transdermal drugdelivery device. That patent further indicates that "kaolin and clay"are fillers with mild acidity which can be used to absorb nitroglycerinto regulate nitroglycerin release. The patent indicates that the use ofthe filler is optional, but that when the filler is used it can be usedin amounts up to two times the amount by weight of the adhesive, withthe drug nitroglycerin representing 1 to 10% by weight of the "wholeamount of the adhesive." The preferred range of filler was indicated tobe from about 0 to 1.2 times the weight of the adhesive, with thenitroglycerin representing 1 to 10% of "the whole amount of theadhesive." Thus in U.S. Pat. No. 4,421,737 the drug nitroglycerin was aminor component of the system. Since nitroglycerin acts as a plasticizerfor the adhesive, increasing amounts lead to increasing tackiness andeventually liquidity. Thus the clay functions as an absorbent for theliquid nitroglycerin to decrease the liquifying effect of thenitroglycerin.

Of increasing interest are transdermal drug delivery devices in whichthe drug is incorporated into a pressure sensitive adhesive, whichserves not only to carry the drug, but to attach the device to the skin.

The introduction of a drug into a pressure sensitive adhesive, asdistinct from carrying the drug in a separate structure of the device,results in a variety of delivery and adhesion problems.

Adhesion problems vary with, among other things, the nature of thepolymers forming the pressure sensitive adhesive, the type and amount ofdrug, the type and amount of other ingredients in the system and theconditions of use.

The transdermal device must be strong enough to adhere to the wearer fora specified length of time. Otherwise the individual will not receivethe prescribed amount of medication. However, if the adhesion is toostrong, the wearer may encounter mechanical irritation upon removal.Adhesiveness of any device varies with time on the skin. Initialadhesion may be adequate. However, when the wearer begins to perspire,adhesiveness may be reduced.

Various attempts have been made to overcome the delivery deficiencyproblems of the prior art transdermal systems. Gels formed ofcrosslinked hydrophilic polyacrylamide and polyvinylpyrrolidone polymershave been used as carriers. However, the single phase gel compositionsdid not lead to systems having acceptable release properties because theduration of release depends upon the density of the gel, which propertyis difficult to control with standard manufacturing techniques. U.S.Pat. No. 4,391,797 attempted to solve such problems, particular forimplants and drugs having a molecular weight of at least 1000 bycombining a relatively water insoluble polymer matrix such as ethylenevinyl acetate copolymer with a swellable, hydrophylic drug having amolecular weight of at least 1000.

It is also known that the inclusion of a solid in an ethylene vinylacetate polymer can result in pore formation. See Grace U.K. PatentSpecification No. 1,126,849.

One aspect of this invention is based on the finding that it is not atall necessary or desirable to control the release of the drug from thepolymer, for example, by a rate limiting membrane, so that there is auniform delivery rate per unit time. Rather, improved results areobtained when the drug is delivered to the skin as rapidly aspracticable, namely where the rate of release is not constant, butdecreases over time. This more rapid release in fact may result inimproved delivery of the drug to the body system as shown by bloodlevels of drug having a more narrow therapeutic range and smaller peakto trough ratios.

Another aspect of this invention is the finding that the addition of aclay to a transdermal drug delivery device, namely a dermal composition,increases the adhesiveness of such device. Specifically, one aspect ofthis invention is the addition of an adhesiveness increasing amount of aclay to a mixture of a drug and a pressure sensitive adhesive,particularly an adhesive containing a solvent for one or more of thecomponents of the composition.

This invention also permits more rapid release of the drug whileincreasing adhesiveness.

The clay is used in an adhesiveness increasing amount, which in anyevent is a minor amount based on the total weight of the composition.The term "a minor amount" used here means less than about 50% andpreferably less than 20% and more preferably less than about 10% or evenabout 5% by weight of the total composition. Use of higher amounts ofclay results in an unacceptable retardation in the release rate of thedrug. Surprisingly, it has been found that the addition of a clayincreases the adhesiveness of a tacky polymer, despite previous reportsthat clay reduces cohesiveness and impliedly adhesiveness.

SUMMARY OF THE INVENTION

This invention resides in the discovery that drugs may be delivered overprolonged periods of time in a highly effective manner using polymermatrixes of limited aqueous and biological fluid solubility and havingat least two phases.

This invention relates to a method of increasing the adhesiveness of ashaped pressure sensitive adhesive. This increase in adhesiveness isachieved by adding an adhesiveness increasing amount of a clay to saidadhesive prior to casting.

This invention also relates to a dermal composition. The adhesive dermalcomposition comprises a mixture of a drug, a pressure sensitiveadhesive, a solvent for one of more of the composition components and aminor amount, namely less than about 50% and preferably less than 20% bydry weight of the total composition, of an adhesiveness increasingamount of a clay.

It has been surprisingly found that the addition of a clay to anadhesive, particularly a mixture of a rubber, an ethylene/vinyl acetateand an acrylic polymer pressure sensitive adhesive formulation, resultsin a pressure sensitive drug composition of desirable peel, adhesion,shear resistance and tack.

The composition can contain other ingredients known for use withtransdermal drug delivery compositions. The device is thus a multiphasecomposition comprising a phase formed of a polymeric matrix havinglimited water solubility containing in admixture therein a drug. Thematrix may be comprised of one or more polymers. The combination of thespecific polymers, liquid solvent and solids, such as drug and a clay,is available to form an interpenetrating phase in the matrix. When thesystem is placed on the skin, the drug is released from the matrix at arapid but decelerating rate.

The clay of this invention can be hydrated aluminum silicate, kaolinite,montmorillonite, atapulgite, illite, bentonite, and halloysite.Preferred clays are those with a three layer structure.

The pressure sensitive adhesive can be any adhesive, which, whencombined with a drug, tends to adhere over the conditions of use. Auseful adhesive is a mixture of a multipolymer and a rubber, especiallya multipolymer containing vinyl acetate and ethylene monomers andacrylic polymer. The rubber can be a natural or synthetic rubber.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the structure of the kaolinite.

FIG. 2 illustrates the structure of montmorillonite.

FIG. 3 illustrates the structure of the octahedral layer of a clay.

FIG. 4 illustrates the structure of the tetrahedral layer of a clay.

DETAILED DESCRIPTION OF THE INVENTION INCLUDING PREFERRED EMBODIMENTS

This invention relates to increasing the adhesiveness of adrug-containing pressure sensitive adhesive, namely a dermalcomposition, by the addition of a clay. The clay is added in anadhesiveness-increasing amount.

This invention also relates to a transdermal drug delivery device orcomposition comprising a drug, a pressure sensitive adhesive, a liquidsolvent for one or more components of the composition and a clay. Theclay is present in an adhesiveness-increasing effective amount, namely aminor amount or less than 50% of the total composition, and preferablyabout 20% or less of the total dry weight of the composition. Morepreferably the clay constitutes less than 10% or even less than 5% byweight of the total composition. The term "dry weight" as used hereinmeans the weight of the composition after casting and drying.

This invention also relates to increasing the rate of drug release bythe use of a multiphase system comprising a phase formed of a polymermatrix having a limited water solubility and an additional phase orphases comprising one or more of the following a polymer, a liquid suchas a solvent and a solid for example a drug or a clay.

The term "clay" as used herein means any natural or synthetic clay andincludes hydrated aluminum silicate, kaolinite, montmorillonite,atapulgite, illite, bentonite, and halloysite. Preferred clays are thosewith a three layer structure.

The term "drug" as used herein means and refers to any substance capableof being administered to the skin of an animal to exert a local orsystemic effect. Thus, the term "drug" can include, but is not limitedto:

1. Anti-infectives, such as antibiotics, including penicillin,tetracycline, chloramphenicol, sulfacetamide, sulfamethazine,sulfadiazine, sulfamerazine, sulfamethizole and sulfisoxazole;antivirals, including idoxuridine; and other anti-infectives includingnitrofurazone and the like;

2. Anti-allergenics such as antazoline, methapyrilene, chlorpheniramine,pyrilamine and prophenpyridamine;

3. Anti-inflammatories such as hydrocortisone, cortisone, dexamethasone,fluocinolone, triamcinolone, medrysone, prednisolone, piroxicam, oxicamand the like;

4. Decongestants such as phenylephrine, naphazoline, andtetrahydrozoline;

5. Miotics and anticholinesterases such as pilocarpine, carbachol, andthe like;

6. Mydriatics such as atropine, cyclopentolate, homatropine,scopolamine, tropicamide, ecuatropine and hydroxyamphetamine;

7. Sympathomimetics such as epinephrine;

8. Sedatives, hypnotics, analgesics and anesthetics such as chloral,pentobarbital, phenobarbital, secobarbital, codeine, lidocaine, fentanyland fentanyl analogs, opiates, opioids, agonists and antagoniststherefor;

9. Psychic energizers such as 3-(2-aminopropyl)indole,3-(2-aminobutyl)indole, and the like;

10. Tranquilizers such as reserpine, chlorpromazine, thiopropazate andbenzodiazepines such as alprazolam, triazolam, lorazepam and diazepam;

11. Androgenic steroids such as methyltestosterone and fluoxymesterone;

12. Estrogens such as estrone, 17-beta-estradiol, ethinyl estradiol, anddiethylstilbestrol;

13. Progestational agents, such as progesterone, 19-norprogesterone,norethindrone, megestrol, melengestrol, chlormadinone, ethisterone,medroxyprogesterone, norethynodrel 17 alpha-hydroxyprogesteronedydrogesterone, and nomegesterol acetate;

14. Other steroids or steroid like substances such as androgens.

15. Humoral agents such as the prostaglandins, for example PGE₁,PGE_(2alpha), and PGF_(2alpha) ;

16. Antipyretics such as aspirin, salicylamide, and the like;

17. Antispasmodics such as atropine, methantheline, papaverine, andmethscopolamine;

18. Anti-malarials such as the 4-aminoquinolines, alpha-aminoquinolines,chloroquine, and pyrimethamine;

19. Antihistamines such as diphenhydramine, dimenhydrinate,perphenazine, and chloropenazine;

20. Cardiovascular agents such as nitroglycerin, isosorbide dinitrate,isosorbide mononitrate, quinidine sulfate, procainamide, flumethiazide,chlorothiazide, calcium antagonists such as nifedipine, verapamil anddiltiazem and selective and non-selective beta blockers such as timolol,salbutamol, terbutaline and propranolol, ACE inhibitors such ascaptopril and various other agents such as clonidine and prazosin.

21. Nutritional agents such as essential amino acids and essential fats.

Other drugs having the same or different physiological activity as thoserecited above can be employed in drug delivery devices within the scopeof the present invention. Although most of the foregoing drugs are solidat room temperature, some drugs are liquid at such temperatures.

Drugs contained in the composition can be in different forms dependingon solubility and release characteristics, such as uncharged molecules,components of molecular complexes or pharmacologically acceptable saltsor derivatives thereof. Simple derivatives of the drugs such aspharmaceutically acceptable ethers, esters, amides, and the like whichhave desirable retention and release characteristics but which areeasily hydrolyzed at body pH, enzymes, pro-active forms, and the likecan be employed.

The amounts of drug for use in the invention are as set forth herein,for example in the accompanying disclosure and examples, and are alsoknown in the art from standard reference books such as Remington'sPharmaceutical Sciences, Seventeenth Edition, Part IV, published by MackPublishing Co., Easton, Pa. and Goodman and Gilman, "The PharmacologicalBasis of Therapeutics", MacMillan Publishing Co., 6th Edition (1980).

The therapeutic dosage and dosage unit amounts for the transdermal routecan be determined by standard tests known to those skilled in the artand an estimation of dosage by the in vitro flux data using humancadaver skin. Alternatively, animal skin can be used to estimate dosagesas described in U.S. Pat. No. 4,751,087.

The term "pressure sensitive adhesive" as used herein means and refersto polymers, including but not limited to homopolymers, copolymers andmixtures of polymers, which are adhesive in the sense that they canadhere to the skin of an animal and which are pressure sensitive in thesense that adherence can be effected by the application of pressure. Thepressure sensitive adhesive can function as a matrix for the drug. Theadhesive is sufficiently resistant to chemical and/or physical attack bythe environment of use so that it remains substantially intactthroughout the period of use. The adhesive is biocompatible in theenvironment of use, plastically deformable and with limited watersolubility solubility. The term "water" as used herein includes watercontaining biological fluids such as saline and buffers.

A wide variety of polymers are known to be suitable for use in pressuresensitive adhesives. Suitable polymers include a natural or syntheticrubber, acryates, polycarboxylic acids or anhydrides thereof, vinylacetate polymers and the like. A pressure sensitive adhesive can becomposed of a single polymer or mixtures thereof. It is generally foundthat the preferred polymers for pressure sensitive applications have aglass transition temperature of between about -50 to +10 degrees Celsius(°C.). The glass transition temperature is related to the molecularweight of the adhesive.

A preferred dermal composition of this invention comprises a drug; amultipolymer comprising an ethylene/vinyl acetate polymer and anacrylate polymer; a rubber, a clay and, optionally, a tackifying agent.The multipolymer and rubber are preferably in a ratio by weightrespectively from about 1:10 to about 30:1, more desirably about 1:5 to20:1 and preferably about 1:2 to 15:1. The ratio of ethylene/vinylacetate polymer to acrylate polymer is preferably about 20:1 to about1:20 by weight. The clay is present in the composition in an amount bydry weight of less than about 50% and preferably from 0.1 to 20%.

The term "solvent," when used to refer to one or more of the componentsof the composition, means a substance added to minimize the lack ofsolubility or dispersibility of one or more of the components in thedermal composition. The solubilities of the components in polar andnon-polar solvents of the composition are either known or can easily bedetermined by known methods.

When a lipophilic drug is used, such as 17-beta estradiol, a fat solublesteroid, the drug has a limited solubility in various polymers used forpressure sensitive adhesives. The addition of a glycol improves thedispersibility of the steroid such as 17-beta estradiol, whilemaintaining the even distribution of the drug throughout the adhesive.However the addition of glycol and various other liquids to thecomposition often results in plasticization and thus a reduction in theadhesiveness of the composition.

The use of clay with a liquid drug or a drug in a liquid solvent mayminimize any loss of adhesiveness, resulting from the inclusion of theliquid.

This system permits a low loading of medicament and solvent into thedermal composition while maintaining the desirable physical propertiesand release rate. The system also permits use of a large amount of drugswhich plasticize the multipolymer.

The composition of this invention possesses sufficient adhesiveproperties to remain in place for days with low incidence of debonding.Surprisingly, the clay increases adhesiveness even though it reducescohesiveness. Generally, changes in cohesiveness are proportional tochanges in adhesiveness.

The transdermal drug delivery device of this invention has a definedgeometric shape, and has a protective release liner on one side and abacking on the other. The shape is achieved by conventional techniques,e.g. by casting or cutting. Removal of the liner exposes the pressuresensitive adhesive. The pressure sensitive adhesive is backed by a drugimpermeable material that may be colored and labeled as appropriate.Suitable release liners and backings are those known in the art for usewith pressure sensitive adhesives.

The composition is especially adapted for use with the delivery of drugswhere the weight of the drug is less than 50% of the total weight of thecomposition, namely where dispersibility is important. The compositionis particularly useful where the weight of the drug is less than 10% oreven less than 5% of the total weight of the composition.

With the present invention, drugs incorporated into the pressuresensitive adhesive are rapidly released to the skin. The fact that thedrug is rapidly released to the skin and may be in a liquid thatfunctions as a solvent, does not in fact negatively affect the rate ofpermeation through the skin and the resulting blood levels of the drug.Rather, the system permits even delivery of the drug to the blood,particularly a steroidal drug, and with less percent fluctuation ofblood levels of drug, namely peak to trough variation, than whencontrolled diffusion is used. When the device of this invention isplaced on the skin, the drug will permeate to and through the skin.

The dermal composition according to the present invention can beprepared, for example, by mixing the adhesive, for example themultipolymer including the acrylate polymer, drug, the rubber, theoptional solvent, clay and optional tackifying agent in an appropriatelower molecular weight liquid. Appropriate liquids are preferablyvolatile polar and non-polar organic liquids, such as an alcohol, suchas isopropyl alcohol or ethanol, a benzene derivative such as xylene ortoluene, alkanes and cycloalkanes such as hexane, heptane andcyclohexane and an alkanoic acid acetate such as an ethyl acetate. Theliquid mixture is cast at ambient pressure and all lower molecularweight liquids removed; for example by evaporation, to form a film. Thehigher boiling solvents such as lower molecular weight alkane diols usedin the composition remain therein.

The ethylene/vinyl acetate polymers can be either a copolymer or aterpolymer. Thus a copolymer of vinyl acetate and ethylene can be used.A terpolymer of an acrylic acid/ethylene/vinyl acetate can also be used.Thus the third monomer of the terpolymer can be an acrylic acid such asacrylic acid or methacrylic acid or copolymers thereof.

The acrylate polymer can be any of the various homopolymers, copolymers,terpolymers and the like of various acrylic acids. The acrylic polymerconstitutes preferably from about 5% to about 95% the total weight ofthe multipolymer, and preferably 25% to 92%, the amount of the acrylatepolymer being chosen being dependent on the amount and type of the drugused. Thus the smaller the amount of the drug used, the greater amountof the acrylate polymer can be used.

The acrylate polymers of this invention are polymers of one or moreacrylic acids and other copolymerizable functional monomers.

The acrylate polymer is composed of at least 50% by weight of anacrylate or alkylacrylate, from 0 to 20% of a functional monomercopolymerizable with the acrylate and from 0 to 40% of other monomers.

Acrylates which can be used include acrylic acid, methacrylic acid andesters thereof, including N-butyl acrylate, n-butyl methacrylate, hexylacrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexylacrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate,dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecylmethacrylate.

Functional monomers copolymerizable with the above alkyl acrylates ormethacrylates which can be used include acrylic acid, methacrylic acid,maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropylacrylate, acrylamide, dimethylacrylamide, acrylonitrile,dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate,tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate,methoxyethyl acrylate and methoxyethyl methacrylate.

Ethylene/vinyl acetate copolymers and terpolymers are well known,commercially available materials. Typically such polymers have a vinylacetate content of about 4 percent to 80 percent by weight and anethylene content of 15 to 90 percent of the total. Preferably theethylene/vinyl acetate copolymer or terpolymer has a vinyl acetatecontent of about 4 percent to 50 percent by weight, with a melt index ofabout 0.5 to 250 grams per ten minutes, and a density having a range ofabout 0.920 to 0.980. More preferably the polymer has a vinyl acetatecontent of about 40 percent by weight and a melt index of about 0.5 to25 grams per ten minutes. Melt index is the number of grams of polymerwhich can be forced through a standard cylindrical orifice under astandard pressure at a standard temperature and thus is inverselyrelated to molecular weight. As is used in the specification, melt indexis determined in accordance with the standard ASTM D 1238-65T conditionE.

In addition to varying the percentage of vinyl acetate in theethylene/vinyl acetate polymer, the properties of the multipolymer canbe changed by varying the amount of acrylate.

From the foregoing it can be understood that the multipolymer can becomposed of an ethylene/vinyl acetate polymer containing at least aboutfrom 15 to 90 percent by weight of ethylene monomer and from about 4 to80 percent by weight of vinyl acetate monomer, and from about 5 to 95%of an acrylate polymer.

The selection of the particular ethylene/vinyl acetate and acrylatemultipolymer, along, with the rubber and other agents will be dependenton the particular drug used and the form in which it is added, drugalone or drug plus solvent. By varying the composition, the release ratecan be modified, as will be apparent to one skilled in the art.

Selection of the particular multipolymer is governed in large part bythe drug to be incorporated in the device, as well as the desired rateof delivery of the drug. Those skilled in the art can readily determinethe rate of delivery of drugs from the polymers and select suitablecombinations of polymer and drug for particular applications.

The term "rubber" as used herein means a natural or syntheticelastomeric polymer. The rubbers useful in the invention include naturallatex (polyisoprene) and carboxylated styrene/butadiene polymers. Othersuitable rubbers include styrene copolymers such asstyrene-isoprene-styrene block copolymer, polybutylene andpolyisobutylene, synthetic polyisoprene, butyl rubber and siliconerubber.

To the extent the tackifying agent is a natural or synthetic rubber,references herein to amounts of a rubber in the composition includes therubber used as a tackifier.

The rubber elastomers are used to promote the adhesiveness of thecomposition. Particularly suitable elastomers include the syntheticrubbers, particularly those having a molecular weight distributionapproximating that of natural rubber latex or natural rubber latexitself.

The ratio by weight of multipolymer to rubber is preferably about 1:10to about 30:1 respectively and more preferably about 1:5 to about 20:1,and even more preferably 1:2 to 15:1, the amount of rubber used beingselected to preferably achieve a tack of 200 to 800 grams per squarecentimeter and more preferably 300 to 500 grams per square centimeter(ASTM D 2979) and adhesion of about 1 to 3 pounds per linear inch (ASTMD 903-49).

In general, the composition should have a glass transition temperature(Tg), measured using a differential scanning calorimeter, of betweenabout -70° C. to 0° C. and be a pressure sensitive adhesive at roomtemperature.

The expression "limited water solubility" of the pressure sensitiveadhesive as used herein denotes the ability of the adhesive to functionin the device of this invention. The phrase means that the polymer has alimited ability to be dissolved in or absorb water and like highly polarliquids. This hydrophobicity is important in the sense that the adhesivebe of limited solubility in water and like biological fluids overprolonged periods of time. One procedure for determining waterabsorption of a given polymer comprises immersing a dry, measuredsection of the polymer in water at 20° C. for 24 hours. After removal ofthe polymer from the water it is reweighed and the weight gain isexpressed as a percent by weight of the polymer, of the water absorbed.Detailed procedures are known to persons skilled in the art.

The transdermal drug delivery device can additionally contain additivessuitable for use with transdermal drug delivery devices such astackifiers, softeners, penetration enhancers and various otheringredients used in transdermal formulations.

The device can also include a filler. Fillers have been used in theadhesive industry to reduce the cost of polymers, increase the specificgravity and to raise the viscosity of adhesive formulations. Variousingredients have been used as fillers including allantoin, zinc oxide,calcium carbonate, sorbitol, silicas, cellulose derivates such asmethylcellulose, carboxymethylcellulose and polyvinyl alcohol. Theaddition of these hydrophilic fillers, emulsifiers and suspending agentshas not been found to improve adhesiveness, as does the addition ofclay.

The amount of drug to be incorporated in the composition variesdepending on the particular drug, the desired therapeutic effect and thetime span for which the device provides therapy. For most drugs, thepassage through the skin will be the rate limiting step. Thus, theamount of drug and the rate of release is typically selected so as toprovide delivery characterized by substantially zero order timedependency for a prolonged period of time. The minimum amount of drug inthe system is selected to deliver the drug at least at the rate at whichthe drug passes through the skin in the time span for which the deviceis to provide therapy. Conveniently, the amount of drug in the systemcan vary from about 0.1 to about 50% by weight. As dosages increase tomore than 50% by weight, wear is seriously affected and generally alarger unit would be used in lieu of an increased amount of drug.

Clays belong to two groups. In the kaolinite group, the mineral ischaracterized by a two-layer (1:1) lattice consisting of one aluminaoctahedral layer linked to one silica tetrahedral layer. This latticedoes not expand with varying water content and no replacement of iron ormagnesium in the octahedral layer are known. The other group of clayminerals is characterized by a three-layer (2:1) lattice. In this typeof lattice an alumina octahedral layer is sandwiched between two silicatetrahedral layers.

As seen in FIG. 1, kaolinite has a two-dimensional structure. As seen inFIG. 2 montmorillonite has a three-dimensional structure, a preferredstructure.

Bentonite, known as purified bentonite, is colloidal montmorilloniteprocessed to remove grit and non-swellable ore components.

Montmorillonite is one of several important clays belonging to thethree-layer group. In montmorillonite these three-layer units areloosely held together in the c-direction, namely the cross-section oraxis perpendicular to the layers, with water and cations between them.Montmorillonite is the principal clay mineral of bentonite. Some of theoutstanding features of montmorillonite are the expandability of thecrystal lattice and the presence of cations between the unit layers. Theamount of water between the layers varies so that the total c-dimensionranges from 9.6 to 21.4 angstrom units. In water, the cations betweenthe unit layers can be exchanged by cations available in solution.Montmorillonite is also capable of forming organic-montmorillonitecomplexes with certain organic molecules.

The amount of clay to be added to the formulation is an adhesivenessincreasing amount of clay up to a maximum amount. The maximum amount isthat which reduces the cohesive strength of the transdermal drugdelivery device resulting in reduced rate of drug delivery or reducedwear time or both. Reduced wear time is lower than required for thedosage form, usually less than 12 hours. In practice although amounts ofclay from about 0.1% to 20% or even up to 50% based on the total weightof the composition may be used, preferred amounts are about 1 to 6%,especially where lower drug and solvent levels are used. Higher amountsof clay results in loss of cohesive strength.

Surprisingly, it has been found that for 17-beta-estradiol, use of thepresent composition (as set forth in Example 1 below) results in notonly an exponential release to the skin, but lowered percent fluctuationof blood level over time.

In order to determine the adhesiveness increasing amount, wear tests areperformed using adhesive-coated strips of the adhesive to be tested onten or more selected individuals. The strips may or may not contain thedrug. In the wear tests, a strip of adhesive is adhered to an individualin the proposed area of use for the prescribed period of time. Theamount of time the strip sticks to the individual is recorded. A stripis considered to be sufficiently adhesive if its duration of adhesion inmost of the individuals is the intended wear time, which can vary from12 hours to one week or more.

The actual percentages of clay for any given polymer system can bedetermined by subjecting various transdermal drug delivery devicescontaining varying amounts of clay to the test previously indicated inthe previous paragraph. The amount of clay is related to the type andpercent by weight of drug and liquids in the system. The actual amountof clay used is typically less than the weight of the liquid.

By adjusting the type and amount of multipolymer, rubber, drug,tackifying agent and clay, it is possible to produce a composition thatcan be effectively utilized as a transdermal drug delivery system. Theinteracting effects of the drug, multipolymer, rubber and tackifyingagent make it possible to improve the stability, adhesion, wear andamount of drug delivery per unit area. The desirable composition isnon-irritating to the skin. Further, the composition should besufficiently adhesive so as to firmly adhere to the skin, even whensubjected to adverse conditions such as humidity, perspiration,movement, showers and/or bathing, but not so adhesive as to causeirritation to the skin or substantial discomfort to the patient whenremoved from the skin. Further, all components used must be compatiblewith the drug.

The composition can also contain agents known to accelerate the releaseof the drug onto the body surface or through the skin. This class ofagents includes those with diverse mechanisms of action including thosewhich have the function of improving the release rate of the drug fromthe multipolymer and those which improve percutaneous absorption. Forexample, absorption, can be accelerated by changing the stratumcorneum's (skin) ability to retain moisture, softening the skin, andimproving the skin's permeability. Absorption can also be achieved bythe agents acting as penetration assistants or hair-follicle openers orchanging the state of the skin including the boundary layer. Some ofthese agents have more than one mechanism of action. Some examples ofthese enhancers are glycols such as diethylene glycol, dipropyleneglycol, butylene glycol, propylene glycol or polyethylene glycol whichmay enhance drug solubility, oils such as olive oil, squalene orlanolin, fatty acid ethers such as cetyl ether and oleyl ether and fattyacid esters such as myristyl proprionate which enhance drugdiffusibility, urea and urea derivatives such as allantoin which affectthe ability of keratin to retain moisture, polar solvents such asdimethyldecylphosphoxide, methyloctyl-sulfoxide, dimethyllaurylamide,dodecylpyrrolidone, iso-sorbitol, dimethylacetonide, dimethylsulfoxide,decylmethylsulfoxide and dimethylformamide which affect keratinpermeability, salicylic acid which softens the keratin, amino acidswhich are penetration assistants, benzyl nicotinate which is a hairfollicle opener, and higher molecular weight aliphatic surfactants suchas lauryl sulfate salts which change the surface state of the skin anddrugs administered. Other agents include linoleic and ascorbic acids,panthenol, butylated hydroxytoluene, propyl oleate and propyl orisopropyl myristates.

Some drugs, such as the vasodilator nitroglycerin, function as aplasticizer because they are soluble to a certain degree in the polymer.For drug molecules which are not readily soluble in the polymer, asolvent for the drug and polymer can be added. Such solvents, such as,lecithin, retinol derivatives, tocopherol, dipropylene glycol,triacetin, propylene glycol, saturated and unsaturated fatty acids,mineral oil, alcohols, butyl benzyl pthalate, and the like are usefulsolvents depending on the solubility of the drug chosen. These solventsare of a volatility that they do not substantially evaporate on dryingof the cast device.

The adhesive layer of the device of this invention is backed by amaterial which prevents the escape of the active ingredient. Thisbacking layer is desirably selectively permeable, for example to oxygen,with a suitable water vapor transmission rate so that the transdermaldrug delivery system will "breathe," allowing the skin to maintain amore natural state. The permeable backing should not permit passage ofthe drug. However the backing layer may be a relatively non-permeablematerial, such as, metal foil (example: aluminum), polyolefin (example:polyethylene or polypropylene), polyester (example: polyethyleneterephthalate), and polyamide.

The device of this invention has an interpenetrating phase comprising anagglomerate or clusters of one or more of polymer, drug, solvent or claythat form a network of substantially contiguous zones in the pressuresensitive adhesive. The network can be a lightly to highly branchedplurality of clusters or it can be a short to long linear chainplurality of clusters.

The rate of release of the drug from the device of this invention can beeasily determined by those skilled in the art by using standardprocedures. In this manner, particular materials used as the pressuresensitive adhesive, as well as the drug, solvent and clay, can bedesigned and programmed for an intended result.

Preferred and optimum compositions are as follows:

                  TABLE                                                           ______________________________________                                        PERCENT BY WEIGHT (dry)                                                                    Optimum    Preferred                                                                              Suitable                                     Component    Amount     Range    Range                                        ______________________________________                                        Rubber       5            2 to 20                                                                              0-90                                         Acrylate     55          25 to 70                                                                              0-90                                         Ethylene-Vinyl                                                                             5            3 to 20                                                                              0-90                                         Acetate                                                                       Polyisobutylene                                                                            13           3 to 20                                                                              0-40                                         Lecithin     3            1 to 10                                                                              0-30                                         Propylene Glycol                                                                           1          0.5 to 10                                                                              0-20                                         Butylene Glycol                                                                            2          0.5 to 10                                                                              0-20                                         Dipropylene Glycol                                                                         1          0.5 to 10                                                                              0-20                                         Oleic Acid   7          0.2 to 10                                                                              0-20                                         Clay         3          0.1 to 6 0.2-20                                                                        to 50                                        Mineral Oil  2          0.5 to 4                                              Drug         3          0.5 to 6 0.5-50                                                    100.0%                                                           ______________________________________                                    

EXAMPLES

In the following examples, "Airflex" refers to a trademark of AirProducts and Chemicals Inc., Allentown, Pa. for a group of optionallycarboxylated vinyl acetate/ethylene polymers in aqueous emulsion."Airflex 416" is a carboxylated vinyl acetate/ethylene terpolymer andhas the following properties:

    ______________________________________                                        Solids              52% min.                                                  Viscosity (cps)     1500-2500                                                 pH                  3.5 to 5                                                  Density             8.8 lbs. per gal.                                         ______________________________________                                    

The same type of polymer, "Airflex 426" has the properties:

    ______________________________________                                        Viscosity (20 rpm) (cps)                                                                            1,000-1,500                                             pH                    4.5-5.0                                                 Tg (°C.)       -5 to 0                                                 Intrinsic Viscosity   0.3-0.4                                                 In Toluene                                                                    Swell Index           17.5-22.5                                               ______________________________________                                    

"Airflex 400", "Airflex 405" and "Airflex 465 DEV" are trademarks of AirProducts and Chemicals Inc., Allentown, Pa. for a group of vinylacetate/ethylene copolymers supplied as aqueous emulsions.

"ADCOTE 72A103" also called "Morstik 103" is a trademark of MortonThiokol, Chicago, Ill. for a styrene butadiene styrene ("S-B-S") blockcopolymer rubber.

"ALCOLEC" is a trademark of American Lecithin Company Atlanta, Ga. forlecithin sold as ALCOLEC 6622 PG 60% by weight in propylene glycol.

"AEROTEX 3730" resin is a trademark of American Cyanamid, Wayne, N.Y.for a melamine formaldehyde crosslinking agent for various functionalgroups, including carboxyl groups having a density of 10.5 lbs. pergallon.

    ______________________________________                                        "AIRFLEX 400" has the following properties:                                   Viscosity       1900-2800 cps @ 20 rpm                                                        (77° F.)                                               Tg              0° C.                                                  pH              4.0 to 5.0                                                    density         8.9 lb per gal.                                               "AIRFLEX 405" has the following properties:                                   Viscosity       300-1000 cps @ 20 rpm                                                         (25° C.)                                               Tg              7° C.                                                  pH              5.0 to 6.0                                                    density         9.0 lb per gal.                                               "AIRFLEX 465 DEV" has the following                                           properties:                                                                   Viscosity       800-1300 cps @ 20 rpm                                                         (77° F.)                                               Tg              -5° C.                                                 pH              4.5 to 5.5                                                    density         9.0 lb per gal.                                               ______________________________________                                    

"DURO-TAK 36-6172" is a trademark of National Starch and ChemicalCorporation, Bridgewater, N.J. for a solution of a resin modifiedstyrene butadiene block copolymer with terpene resins and rosin esterresins having softening points of 100° C.

"DURO-TAK 80-1194 and 80-1196 and 80-1054" are trademarks of NationalStarch for polyacrylates in organic solution. "DURO-TAK 80-1194 and80-1196" consist of methacrylic acid, 0-3%, butylacrylate,2-ethylhexylacrylate and other monomers, such as vinyl acetate.

"ELVAX 40-W" is a trademark of Dupont for an ethylene/vinyl acetatepolymer which has the following typical properties:

    ______________________________________                                        Vinyl Acetate (VAc) Content, % by weight                                                              40                                                    Inherent Viscosity @ 30° C.                                                                    0.70                                                  (0.25 g/100 ml. toluene)                                                      Melt Index, g/10 min.   57                                                    (ASTM D 1238, modified)                                                       Residual VAc Monomer, % by wt. 1                                                                      less than                                                                     about 0.3                                             Odor                    Slight                                                Antioxidant, ppm BHT    550                                                   Tensile Strength.sup.a, MPa                                                                           4.8-6.2                                               (psi)                   (750-900)                                             Elongation at Break.sup.a, %                                                                          1000-1300                                             Elastic (Tensile) Modulus.sup.a,b, MPa                                                                3.0                                                   (psi)                   (450)                                                 Density @ 23° C. (73° F.), kg/m.sup.3                                                   965                                                   (ASTM D 1505) (G/cm.sup.3)                                                                            (0.965)                                               Hardness, Shore A-2 Durometer,                                                                        40                                                    10 sec (ASTM D 2240)                                                          Softening Point, Ring and Ball, °C.                                                            104                                                   (ASTM E 28) (°F.)                                                                              (220)                                                 ______________________________________                                         .sup.a ASTM D 1708; samples die cut from pressed films; gage dimensions       2.23 cm × 0.47 cm × 0.13 cm (0.876 in × 0.187 in .times     0.050 in); crosshead speed 5.1 cm (2 in)/min.                                 .sup.b Modulus calculated as in ASTM D 638.                              

"ESCOREZ RESIN 1310LC and 2101 and 2393" are a trademark of ExxonChemical Company, Baton Rouge, La. for aliphatic (1310LC) andaliphatic/aromatic (2101 & 2393) resins functioning as a tackifier.

"EXXON 108A" emulsion is the trademark of Exxon Chemical Company, BatonRouge, La. for an aliphatic petroleum resin tackifying agent having aglass transition temperature of 40° C., a pH of 7.0 and an averageparticle size of 0.33 microns, and an anionic particle charge.

"EXXON 109A" emulsion is the trademark of Exxon Chemical Company, BatonRouge, La. for a mixed aromatic/aliphatic petroleum resin tackifyingagent in an aqueous emulsion having a glass transition temperature (Tg)at 37° C., a pH of 7.0, with an average particle size of 0.5 microns andan anionic particle charge.

"EXXON 346" is a trademark of Exxon Chemical Company for a mixedaromatic/aliphatic petroleum resin tackifying agent having a Tg of 25°C., a pH of 7.0, an average particle size of 0.35 microns and an anionicparticle charge.

"FLEXBOND 150" is a trademark of Air Products and Chemicals, Inc.,Allentown, Pa. for a polyvinylacetate polymer which is a pressuresensitive emulsion which can function as a tackifying agent.

"HARTEX 103" is a trademark of Firestone Synthetic Rubber and LatexCompany for low-ammonia natural latex (rubber) containing 0.036% sodiumdimethyldithiocarbamate and 0.036% zinc oxide as a preservative. Theproperties of this latex are as follows:

    ______________________________________                                        Total Solids           62.1 ± 0.3                                                                 61.5 min.                                              Dry Rubber Content, %  60.0 min.                                              TS minus DRC, %        1.75 max.                                              Total Alkalinity, % NH .24 ± .02                                           on wet weight                                                                 KOH Number             0.55 ± 0.05                                         Mechanical Stability, sec.                                                                           1400 ± 300                                          Volatile Fatty Acid, % .05 max.                                               pH                     .8 ± 0.20                                           Sludge Content, % on weight                                                                          .03 max.                                               ______________________________________                                    

"HATCOL 200" is a trademark of Hatco Chemical Company, Fords, N.J., fora high molecular weight synthetic ester plasticizer having a molecularweight of 546 and a viscosity @ 20° C. of 300 CPS.

"KORTHIX H-NF" is a trademark of Kaopolite, Inc., Union, N.J. forbentonite, a purified colloidal aluminum silicate (clay).

"NOVEN 109A" is a trademark of Noven Pharmaceuticals, Inc., Miami, Fla.,for the combination of 140 parts of the anhydrous resin Exxon 109A, 70parts toluene and 7 parts Triton X-100. TRITON X-100 is a trademark ofRohm and Haas Company for the water soluble, anhydrous, nonionicsurfactant octylphenoxypolyethoxyethanol with an average of 10 moles ofethylene oxide, having a viscosity of 240 cps @ 25° C. (Brookfield), apour point of 7° C. or 45° F., a specific gravity of 1.065 @ 25° C. anda density of 8.9 lb. per gallon.

"PSA 578A" is a trademark of Dow Chemical, Midland, Mich. forcarboxylated styrene/butadiene containing a bactericide and astabilizer. The formulation has a boiling point of 100° C., a vaporpressure of 17.5 millimeters of mercury at 20° C., a Tg. at -44° C. avapor density of 0.624 at 80° F., is supplied in emulsion form with amilky white liquid appearance and has a specific gravity of 0.980-1.040.

"Santicizer 160" is a trademark of Monsanto, St. Louis, Mo. for butylbenzyl phthalate.

"VISTANEX LM-MS-LC" is trademark of Exxon Chemical Company, Houston,Tex. for a polyisobutylene having a Flory molecular weight of 37,000minimum by AMS Test Method 77-005, a specific gravity of 0.91 and aBrookfield Viscosity, CPS @ 350° F., of 26,000 to 35,000 by ASTM TextMethod 03236.

Nitroglycerin can be supplied as glyceryltrinitrate available in anethanol solution from Imperial Chemical Industries.

All the polymeric ingredients used in the examples are supplied or usedas aqueous emulsions or as solutions wherein the percent solids are asfollows:

    ______________________________________                                                        Percent Solids                                                Ingredient      (by weight)                                                   ______________________________________                                        Airfiex 400       55%                                                         Airflex 405     55                                                            Airflex 416     52                                                            Airflex 426     60                                                            Airfiex 465     66                                                            Hartex 103        61.5                                                        PSA 578A        49                                                            Exxon 108A      57                                                            Exxon 109A      57                                                            Exxon 346       57                                                            Elvax 40W       30                                                            Noven 109A      35                                                            Flexbond 150    55                                                            Aerotex 3730    83                                                            Duro-Tak 36-6172                                                                              56                                                            Duro-Tak 80-1194                                                                              45                                                            Duro-Tak 80-1054                                                                              48                                                            Duro-Tak 80-1196                                                                              45                                                            Adcote 72A103   45                                                            (Morstik 103)                                                                 Vistanex        30                                                            ______________________________________                                    

The general method of preparation of the adhesive is per the followingsteps:

1. Appropriate amounts of adhesive, e.g. rubber, tackifying agent andadhesive multipolymer are combined, and thoroughly mixed together in avessel; since pressure sensitive adhesive formulations are typicallysupplied as emulsions or solutions, the preparation of the compositionis typically performed in liquid solution or suspension, but can as wellbe formed by methods not requiring the presence of a liquid as discussedherein.

2. The heterogeneous mixture is then transferred to a vessel where thedrug or drug and cosolvent and clay are to be added;

3. The drug, solvent, and clay are then added to the heterogenousmixture and agitation is carried out until the mixture and drug form asmooth, heterogeneous mix;

4. The heterogeneous mix containing the drug is then transferred to anadhesive mixing vessel;

5. The mix containing the drug can then be combined with a crosslinkingagent and any additional optional ingredients and thoroughly agitated;

6. The adhesive containing the drug is then transferred to a coatingoperation;

7. The adhesive composition containing the drug is now in a form to makeup the adhesive layer to be coated onto a release liner. When theadhesive composition has been coated onto the release liner, the unit isthen passed into an oven in order to drive off the solvents and/or waterwhich may have been included in the mixing procedure; and after thisoperation is completed and the solvents are removed, theadhesive-component layer will be joined to the backing material and theunit can be wound into rolls for storage.

The order of steps, the amount of the ingredients, pH, and the amountand time of agitation or mixing may be important to avoiding clumpingtogether of the components. These factors can be adjusted by thoseskilled in the art, while keeping in mind the object of providing asmooth, heterogeneous mix.

A number of other methods, including changing some of the order ofsteps, can be carried out and will give desirable results.

In addition to having various shapes, the dosage units produced may comein various sizes. A surface area in the range of 1 to 200 squarecentimeters is contemplated and the presently contemplated, preferredsizes are: 5, 10, 15, 20, 30, 40 and 60 square centimeters. The presentinvention allows incorporation of the amount of drug that is sufficientto deliver the required dose, no greater than the amount that wouldyield undesirable properties.

The present invention is further illustrated by the following examples,which should not be considered to limit the invention.

In the following examples parts are given as parts by weight, of thefinal composition, dry weight.

Example 1

30% ETHYLENE VINYL ACETATE MIXTURE

Twenty eight parts of toluene is weighed and dispensed into a cleanstainless steel kettle. Agitation is started at 44 revolutions perminute ("RPM"). Heating is started with temperature controlled between120° and 125° F. Twelve parts of ethylene vinyl acetate copolymer (Elvax40W) is weighed and added to the kettle through the upper hatch whilemixing and heating continues. The material is mixed for a minimum of twohours from the time aforementioned temperature is reached. The mixtureis transferred to clean containers which are tightly sealed.

30% POLYISOBUTYLENE MIXTURE

Twenty-eight parts of toluene are weighed and dispensed into a cleanstainless steel kettle. Agitation is started at 44 RPM's. Heating isstarted with temperature control set between 145° and 150° F. Twelveparts of polyisobutylene are weighed and added to the kettle whilemixing and heating continues. The material is mixed for a minimum of twohours from the time aforementioned temperature is reached. The mixtureis transferred to clean containers.

BULK ADHESIVE

The following ingredients are mixed: 732 parts of the 30% ethylene vinylacetate mixture prepared as above, 1899 parts of the 30% polyisobutylenemixture prepared as above, 487 parts of S-B-S block copolymer (Adcote72A103; Morstik 103), 307 parts of oleic acid NF, 88 parts of mineraloil USP and 250 parts of 60% lecithin in propylene glycol (Alolec662/PG).

The above ingredients are agitated for a minimum of 10 minutes at 44RPM. To the foregoing mixture, 5223 parts of acrylic polymer (Duro Tak80-1196) is added. Heating is started with temperature set between 120°and 125° F. and the material is agitated for a minimum of 30 minutes,then 145 parts of clay, namely bentonite N.F. are added portionwise toensure complete mixing. To the resulting mixture is added an intimatemixture of 702 parts of 1,3-butylene glycol, 44 parts of dipropyleneglycol and 123 parts of micronized 17-beta-estradiol USP.

COATING

A specified amount of the bulk adhesive is coated on a silicone coatedrelease liner and most of the low boiling solvents associated with thebulk processing removed, and the dried adhesive is laminated to abacking.

The resulting composition has the following ingredients in the indicatedamount.

    ______________________________________                                        COMPONENT       PERCENT BY WEIGHT (dry)                                       ______________________________________                                        1.  Rubber (ADCOTE  5.0                                                           72A103)                                                                   2.  Acrylic (Duro-Tak                                                                             53.7                                                          80-1196)                                                                  3.  Ethylene Vinyl Acetate                                                                        5.0                                                           (ELVAX 40W)                                                               4.  Polyisobutylene (Vistanex                                                                     13.0                                                          LM-MS-LC)                                                                 5.  Oleic Acid      7.0                                                       6.  Lecithin        3.4                                                       7.  Propylene Glycol                                                                              0.4                                                       8.  Dipropylene Glycol                                                                            0.5                                                       9.  Butylene Glycol 4.0                                                       10. Clay (Korthix H-NF)                                                                           3.3                                                       11. Mineral Oil     2.0                                                       12. 17-beta-Estradiol                                                                             2.7                                                                           100.0                                                     ______________________________________                                    

SLITTING

In order to yield the maximum utilization of the rolls of laminate, theyare slit to a specified width according to the size of the patch to bepunched.

PUNCH, POUCH, AND PACKAGING

The role is cut to the desired shape by use of an appropriate shaped dieand the resulting device packaged.

In the following examples, the method of Example 1 is used with theappropriate starting material to yield compositions having the followingcompositions:

Example 2

    ______________________________________                                        COMPONENT        PERCENT BY WEIGHT (dry)                                      ______________________________________                                        1.  Rubber           5.0                                                          (ADCOTE 72A103)                                                           2.  Acrylic (Duro-Tak 80-1194)                                                                     51.0                                                     3.  Ethylene Vinyl Acetate                                                                         5.0                                                          (ELVAX 40W)                                                               4.  Polyisobutylene  12.0                                                         (Vistanex LM-MS-LC)                                                       5.  Oleic Acid       7.0                                                      6.  Lecithin         7.5                                                      7.  Butylene Glycol  7.0                                                      9.  Clay (Korthix H-NF)                                                                            3.0                                                      10. 17-beta-Estradiol                                                                              2.5                                                                           100.0                                                    ______________________________________                                    

Example 3

    ______________________________________                                        COMPONENT        PERCENT BY WEIGHT (dry)                                      ______________________________________                                        1.    Rubber         5.0                                                            (ADCOTE 72A103)                                                         2.    Acrylic        53.0                                                           (Duro-Tak 80-1194)                                                      3.    Ethylene Vinyl 5.0                                                            Acetate (ELVAX 40W)                                                     4.    Polyisobutylene                                                                              12.0                                                           (Vistanex LM-MS-LC)                                                           Oleic Acid     7.0                                                      6.    Lecithin       4.5                                                      7.    Propylene Glycol                                                                             3.0                                                      8.    Butylene Glycol                                                                              3.0                                                      9.    Dipropylene Glycol                                                                           2.0                                                      10.   Clay (Korthix H-NF)                                                                          3.0                                                      11.   17-beta-Estradiol                                                                            2.5                                                                           100.0                                                    ______________________________________                                    

Example 4

    ______________________________________                                        COMPONENT          PERCENT BY WEIGHT                                          ______________________________________                                        1.    Rubber (ADCOTE 72A103)                                                                         5.0                                                    2.    Acrylic (Duro-Tak 80-1194)                                                                     52.0                                                   3.    Ethylene Vinyl Acetate                                                                         5.0                                                          (ELVAX 40W)                                                             4.    Polyisobutylene  12.0                                                         (Vistanex LM-MS-LC)                                                     5.    Oleic Acid       7.0                                                    6.    Lecithin         4.5                                                    7.    Propylene Glycol 3.0                                                    8.    Dipropylene Glycol                                                                             6.0                                                    9.    Clay (Korthix H-NF)                                                                            3.0                                                    10.   17-beta-Estradiol                                                                              2.5                                                                           100.0                                                  ______________________________________                                    

Example 5

    ______________________________________                                        COMPONENT          PERCENT BY WEIGHT                                          ______________________________________                                        1.    Rubber (ADCOTE 72A103)                                                                         5.0                                                    2.    Acrylic (Duro-Tak 80-1194)                                                                     52.0                                                   3.    Ethylene Vinyl Acetate                                                                         5.0                                                          (ELVAX 40W)                                                             4.    Polyisobutylene  12.0                                                         (Vistanex LM-MS-LC)                                                     5.    Oleic Acid       7.0                                                    6.    Lecithin         4.5                                                    7.    Propylene Glycol 3.0                                                    8.    Butylene Glycol  5.0                                                    9.    Dipropylene Glycol                                                                             1.0                                                    10.   Clay (Korthix H-NF)                                                                            3.0                                                    11.   17-beta-Estradiol                                                                              2.5                                                                           100.0                                                  ______________________________________                                    

Example 6

    ______________________________________                                        COMPONENT          PERCENT BY WEIGHT                                          ______________________________________                                        1.    Rubber (ADCOTE 72A103)                                                                         5.0                                                    2.    Acrylic (Duro-Tak 80-1194)                                                                     47.0                                                   3.    Ethylene Vinyl Acetate                                                                         5.0                                                          (ELVAX 40W)                                                             4.    Polyisobutylene  12.0                                                         (Vistanex LM-MS-LC)                                                     5.    Oleic Acid       7.0                                                    6.    Lecithin         4.5                                                    7.    Propylene Glycol 10.0                                                   8.    Butylene Glycol  3.0                                                    9.    Clay (Korthix H-NF)                                                                            3.0                                                    10.   Mineral Oil      1.0                                                    11.   17-beta-Estradiol                                                                              2.5                                                                           100.0                                                  ______________________________________                                    

Example 7

    ______________________________________                                        COMPONENT          PERCENT BY WEIGHT                                          ______________________________________                                        1.    Rubber (ADCOTE 72A103)                                                                         5.0                                                    2.    Acrylic (Duro-Tak 80-1194)                                                                     49.0                                                   3.    Ethylene Vinyl Acetate                                                                         5.0                                                          (ELVAX 40W)                                                             4.    Polyisobutylene  12.0                                                         (Vistanex LM-MS-LC)                                                     5.    Oleic Acid       7.0                                                    6.    Lecithin         4.5                                                    7.    Propylene Glycol 8.0                                                    8.    Butylene Glycol  3.0                                                    9.    Clay (Korthix H-NF)                                                                            3.0                                                    10.   Mineral Oil      1.0                                                    11.   17-beta-Estradiol                                                                              2.5                                                                           100.0                                                  ______________________________________                                    

Example 8

    ______________________________________                                        COMPONENT          PERCENT BY WEIGHT                                          ______________________________________                                        1.    Rubber (ADCOTE 72A103)                                                                         5.0                                                    2.    Acrylic (Duro-Tak 80-1194)                                                                     51.0                                                   3.    Ethylene Vinyl Acetate                                                                         5.0                                                          (ELVAX 40W)                                                             4.    Polyisobutylene  12.0                                                         (Vistanex LM-MS-LC)                                                     5.    Lecithin         4.5                                                    6.    Propylene Glycol 6.0                                                    7.    Butylene Glycol  3.0                                                    8.    Oleic Acid       6.0                                                    9.    Clay (Korthix H-NF)                                                                            3.0                                                    10.   Mineral Oil      2.0                                                    11.   17-beta-Estradiol                                                                              2.5                                                                           100.0                                                  ______________________________________                                    

Example 9

    ______________________________________                                        COMPONENT          PERCENT BY WEIGHT                                          ______________________________________                                        1.    Rubber (ADCOTE 72A103)                                                                         5.0                                                    2.    Acrylic (Duro-Tak 80-1194)                                                                     51.0                                                   3.    Ethylene Vinyl Acetate                                                                         5.0                                                          (ELVAX 40W)                                                             4.    Polyisobutylene  12.0                                                         (Vistanex LM-MS-LC)                                                     5.    Lecithin         4.5                                                    6.    Propylene Glycol 7.0                                                    7.    Butylene Glycol  3.0                                                    8.    Oleic Acid       6.0                                                    9.    Clay (Korthix H-NF)                                                                            3.0                                                    10.   Mineral Oil      1.0                                                    11.   17-beta-Estradiol                                                                              2.5                                                                           100.0                                                  ______________________________________                                    

Example 10

    ______________________________________                                        COMPONENT          PERCENT BY WEIGHT                                          ______________________________________                                        1.    Rubber (ADCOTE 72A103)                                                                         5.0                                                    2.    Acrylic (Duro-Tak 80-1194)                                                                     50.5                                                   3.    Ethylene Vinyl Acetate                                                                         5.0                                                          (ELVAX 40W)                                                             4.    Polyisobutylene  12.0                                                         (Vistanex LM-MS-LC)                                                     5.    Oleic Acid       7.5                                                    6.    Lecithin         4.5                                                    7.    Propylene Glycol 7.0                                                    8.    Butylene Glycol  3.0                                                    9.    Clay (Korthix H-NF)                                                                            3.0                                                    10.   17-beta-Estradiol                                                                              2.5                                                                           100.0                                                  ______________________________________                                    

Example 11

    ______________________________________                                        COMPONENT          PERCENT BY WEIGHT                                          ______________________________________                                        1.    Rubber (ADCOTE 72A103)                                                                         5.0                                                    2.    Acrylic (Duro-Tak 80-1194)                                                                     53.0                                                   3.    Ethylene Vinyl Acetate                                                                         5.0                                                          (ELVAX 40W)                                                             4.    Polyisobutylene  12.0                                                         (Vistanex LM-MS-LC)                                                     5.    Oleic Acid       5.0                                                    6.    Lecithin         4.5                                                    7.    Propylene Glycol 7.0                                                    8.    Butylene Glycol  3.0                                                    9.    Clay (Korthix H-NF)                                                                            3.0                                                    10.   17-beta-Estradiol                                                                              2.5                                                                           100.0                                                  ______________________________________                                    

Example 12

    ______________________________________                                        COMPONENT          PERCENT BY WEIGHT                                          ______________________________________                                        1.    Rubber (ADCOTE 72A103)                                                                         5.0                                                    2.    Acrylic (Duro-Tak 80-1196)                                                                     47.0                                                   3.    Ethylene Vinyl Acetate                                                                         5.0                                                          (ELVAX 40W)                                                             4.    Polyisobutylene  12.0                                                         (Vistanex LM-MS-LC)                                                     5.    Oleic Acid       7.0                                                    6.    Lecithin         4.5                                                    7.    Propylene Glycol 4.0                                                    8.    Dipropylene Glycol                                                                             5.0                                                    9.    Butylene Glycol  3.0                                                    10.   Clay (Korthix H-NF)                                                                            3.0                                                    11.   Mineral Oil      2.0                                                    12.   17-beta-Estradiol                                                                              2.5                                                                           100.0                                                  ______________________________________                                    

Example 13

    ______________________________________                                        COMPONENT          PERCENT BY WEIGHT                                          ______________________________________                                        1.    Rubber (ADCOTE 72A103)                                                                         5.0                                                    2.    Acrylic (Duro-Tak 80-1196)                                                                     51.0                                                   3.    Ethylene Vinyl Acetate                                                                         5.0                                                          (ELVAX 40W)                                                             4.    Polyisobutylene  12.0                                                         (Vistanex LM-MS-LC)                                                     5.    Oleic Acid       7.0                                                    6.    Lecithin         4.5                                                    7.    Propylene Glycol 5.0                                                    8.    Dipropylene Glycol                                                                             6.0                                                    9.    Clay (Korthix H-NF)                                                                            3.0                                                    10.   Mineral Oil      1.0                                                    11.   17-beta-Estradiol                                                                              2.5                                                                           100.0                                                  ______________________________________                                    

Example 14

    ______________________________________                                        COMPONENT          PERCENT BY WEIGHT                                          ______________________________________                                        1.    Rubber (ADCOTE 72A103)                                                                         5.0                                                    2.    Acrylic (Duro-Tak 80-1196)                                                                     48.0                                                   3.    Ethylene Vinyl Acetate                                                                         5.0                                                          (ELVAX 40W)                                                             4.    Polyisobutylene  12.0                                                         (Vistanex LM-MS-LC)                                                     5.    Oleic Acid       7.0                                                    6.    Lecithin         4.5                                                    7.    Propylene Glycol 5.0                                                    8.    Dipropylene Glycol                                                                             6.0                                                    9.    Clay (Korthix H-NF)                                                                            3.0                                                    10.   Mineral Oil      2.0                                                    11.   17-beta-Estradiol                                                                              2.5                                                                           100.0                                                  ______________________________________                                    

The dosage unit of the present invention can be produced in a number ofways. It is particularly important to form the adhesive layer in aseries of steps, with proper agitation and pH adjustment when necessary,so as to avoid coagulation and clumping together of any of thecomponents. After the adhesive layer is formed, the composition makingup this layer can be placed in contact with the backing layer in anymanner known to those skilled in the art in order to produce thetransdermal dosage system. The transdermal dosage system can be producedas follows:

Generally speaking, known methods of producing adhesive tapes can beused for the composition of this invention. These known methodsincluding calender coating method, hot melt coating method, solutioncoating method, emulsion coating method and radiation cured coatingmethods. When dealing with explosive or easily degraded drugs such asnitroglycerin, the solution or emulsion coating method is preferred tominimize the risk of explosion or degradation.

In the calender coating method, the multipolymer, rubber, tackifier andother ingredients are kneaded homogeneously using open rolls, kneaders,internal mixers, and the like. The materials of high viscosity have tobe kneaded at elevated temperatures, usually 90° to 120° C. under highshear rate (1×10 to 5×10³ sec.⁻¹). In the hot melt coating method thesubstances with high thermal plasticity are added to the adhesives andthe adhesives are coated at high velocity. In the emulsion coatingmethod, the emulsion of the ingredients is added to the appropriatecoating head and the excess solvent removed. The solution coating methodis essentially the same as the emulsion coating method, except that themixture is in solution rather than in an emulsion.

The backing member for the adhesive includes plastic films ofpolyethylene, vinyl acetate resins, ethylene/vinyl alcohol,ethylene/vinyl acetate copolymers, polyvinyl chloride, polyurethane, andthe like, metal foils, for example aluminum foil, and the like,non-woven fabric, cloth and laminate films composed of cloth or paperand a basic film. The backing material preferably has a thickness offrom 2 to 1,000 micrometers so as to have good handling properties and"feel". A total thickness of the film-like adhesive material on thebacking member preferably ranges from 12 to 250 micrometers. Compositeproducts having a total thickness less than 14 micrometers may have poorhandling properties.

What is claimed is:
 1. A dermal composition comprising a mixture of 0.1to 50 by dry weight of a drug, a pressure sensitive adhesive, a liquidsolvent for one or more of the components of the composition and about0.1 to about 10% by dry/weight of the total composition of clay toincrease the adhesiveness of the composition.
 2. The composition ofclaim 1, in which the clay is selective from the group consisting ofhydrated aluminum silicate, kaolinite, montmorillonite, atapulgite,illite, bentonite, and halloysite.
 3. The composition of claim 2,wherein said adhesive comprises a multipolymer containing vinyl acetateand ethylene monomers, and an acrylic polymer and a natural or syntheticrubber.
 4. The composition of claim 3 in which the clay is bentonite. 5.A composition of claim 1 comprising 17-beta-estradiol, a pressuresensitive adhesive, a lower molecular weight glycol and an adhesivenessincreasing amount of clay.
 6. The transdermal drug delivery device ofclaim 5 comprising an adhesiveness increasing effective amount ofbentonite.
 7. The composition of claim 1, comprising 17-beta-estradiol,a multipolymer containing acrylate and ethylene vinyl acetate monomers,a natural or synthetic rubber and a clay.
 8. The composition of claim 7in which the clay is selected from the group consisting of hydratedaluminum silicate, kaolinite, montmorillonite, atapulgite, illite,bentonite, and halloysite.
 9. The composition of claim 8, additionallycomprising a solvent for the 17-beta-estradiol.
 10. The composition ofclaim 7, which comprises as approximate percent by dry weight, 0.5 to50% of the drug, 10 to 90% of the multipolymer, 2% to 20% of a rubber,0.5 to 10% of a clay and 0.5 to 10% of a solvent for the drug.
 11. Thecomposition of claim 10 which comprises about 0.5% to about 3% dryweight of a clay.
 12. A multi-phase dermal composition comprising afirst phase comprising a pressure sensitive adhesive and in admixturetherewith, one or more additional phases containing a polymer, 0.1 to50% by dry weight of the composition of drugs, a solvent for one or moreof the components of the composition and about 0.1 to about 10% by dryweight of the composition of clay.
 13. The composition of claim 12, inwhich the clay is selected from the group consisting of hydratedaluminum silicate, kaolinite, montmorillonite, atapulgite, illite,bentonite, and halloysite.
 14. The composition of claim 13 whichcomprises a drug, a multipolymer containing vinyl acetate and ethylenemonomers, an acrylic polymer, a natural or synthetic rubber and aglycol.
 15. The composition of claim 13, in which the clay is bentonite.16. The composition of claim 13 in which the clay is present in anamount of from about 0.5 to about 3% by dry weight.
 17. The compositionof claim 12 in which the clay is present in an amount of from about 0.5to about 3% by dry weight.
 18. The composition of claim 13, in which thedrug is 17-beta-estradiol.
 19. The composition of claim 14, in which thedrug is 17-beta-estradiol.
 20. The composition of claim 15, in which thedrug is 17-beta-estradiol.
 21. The composition of claim 16, in which thedrug is 17-beta-estradiol.
 22. The composition of claim 17, in which thedrug is 17-beta-estradiol.
 23. A dermal composition of claim 1, whereinthe drug is selected from one or more of the group consisting of anestrogen and nitroglycerin.
 24. A dermal composition of claim 1, whichis free of water.
 25. A dermal composition of claim 12, wherein the drugis selected from the group consisting of an estrogen and nitroglycerinand mixtures thereof.
 26. A dermal composition of claim 12, which isfree of water.
 27. A dermal composition comprising a pressure sensitiveadhesive, 0.1 to 50% by dry weight of drug, and about 0.1 to 6% by dryweight of clay to increase the adhesiveness of the composition.
 28. Adermal composition of claim 27, wherein the drug is selected from one ormore of the group consisting of an estrogen and nitroglycerin.
 29. Adermal composition of claim 27, which is substantially free of water.30. A dermal composition of claim 27, which contains a drug-impermeablebacking on a first side of said dermal composition and a protectiverelease liner on a second side which is opposite said first side of saiddermal composition.